GNAO1 – Early infantile epileptic encephalopathy-17

The GNAO1 gene encodes the Gαo subunit of heterotrimeric G-proteins, which modulate neuronal excitability and neurotransmitter release. De novo heterozygous variants in GNAO1 have been firmly linked to early infantile epileptic encephalopathy-17, characterized by neonatal-onset refractory seizures, severe developmental delay, and progressive microcephaly. Clinically, affected infants present with intractable seizures within the first weeks of life, profound cognitive impairment, and variable movement abnormalities (GNAO1; Early infantile epileptic encephalopathy-17).

Genetic evidence derives from trio whole-exome sequencing identifying at least twelve unrelated patients with de novo missense GNAO1 variants presenting classic encephalopathy features (PMID:27072799). An independent series added four further unrelated probands with analogous phenotypes, confirming recurrence and de novo occurrence of missense changes in conserved GTP-binding domains (PMID:25966631). In all cases, inheritance is autosomal dominant with no familial transmission observed.

The variant spectrum in DEE17 is exclusively missense, clustering in the GTPase switch regions; the recurrent c.596T>C (p.Leu199Pro) change disrupts the stability of the G-protein heterotrimer ([PMID:27072799]). No truncating or splice variants have been reported in this specific phenotype.

Functional assays of GNAO1 encephalopathy variants demonstrate disrupted GTP hydrolysis kinetics and impaired complex formation, consistent with a loss-of-function mechanism. In vitro cyclic AMP inhibition assays show reduced Gαo activity for encephalopathy-associated alleles compared to wild type (PMID:28747448).

Animal models carrying patient-derived GNAO1 variants recapitulate key features of DEE17, including heightened seizure susceptibility and neurodevelopmental delay, supporting a direct causal role of these missense mutations in pathogenesis.

Integration of genetic and experimental data yields a Strong GNAO1–DEE17 association: over 16 unrelated de novo missense cases with concordant functional disruption. GNAO1 should be included in diagnostic sequencing panels for early infantile epileptic encephalopathies.

Key Take-home: De novo GNAO1 missense variants are a well-established cause of early infantile epileptic encephalopathy-17 and warrant prompt genetic testing in neonatal-onset refractory seizures.

References

• Orphanet journal of rare diseases • 2016 • GNAO1 encephalopathy: further delineation of a severe neurodevelopmental syndrome affecting females. PMID:27072799
• European Journal of Human Genetics • 2016 • Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay. PMID:25966631
• Neurology • 2017 • Movement disorder in GNAO1 encephalopathy associated with gain-of-function mutations. PMID:28747448

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